Homocyst(e)ine is a risk factor for vascular disease that is independent of and similar in magnitude to that from cholesterol. Currently, several clinical trials are under way world-wide to evaluate the prevention of recurrence of coronary artery disease by high doses of folic acid (0.8 to 5.0 mg/d). To be utilized folic acid, which is not found to a significant extent in nature, must be converted in the body to the active tetrahydrofolates via the action of dihydrofolate reductase. Unreduced folic acid has been previously observed in blood and urine when given orally above doses of 200 ug However, inter-individual variations in the extent to which folic acid remains unmetabolized or excreted have not been well characterized, especially with pharmacologic doses. Moreover, there is evidence to suggest that unreduced folic acid may interfere with homocysteine metabolism to methionine. The purpose of this proposal is to examine the accumulation and rate of clearance of unreduced folic acid in the plasma of healthy subjects given oral doses of folic acid ranging from 0.4mg to 5.0 mg, to measure the percent of the dose excreted unmetabolized into the urine, and any change in plasma total homocyst(e)ine over the course of 24 hours. In addition, the relation between levels of unmetabolized folic acid and non-response or paradoxical response of homocyst(e)ine in subjects chronically taking folic acid at different doses will be investigated. The literature suggests that there is little improvement in the level of homocyst(e)ine above 0.4 mg/d even up to 5 mg/d. A hypothesis to be tested is that this may, in part, be due to the limited ability of some people to convert folic acid to the active tetrahydrofolates. Moreover, folate utilizing enzymes may be inhibited by unmetabolized folic acid, as has already been observed in vitro. We propose to establish what percentage of the population cannot rapidly convert folic acid to the active folate forms, and of these what percentage have elevated homocyst(e)ine levels related to the accumulation of unmetabolized folic acid. Identifying this particular population of individuals may allow treatment of hyperhomocysteinemia to be more fully optimized.